Sorafenib is a potent multi-kinase inhibitor for the treatment of patients with unresectable hepatocellular carcinoma (HCC). However, systemic exposures can lead to severe toxicities. Sorafenib dose often must be reduced or administration discontinued altogether. Microsphere drug delivery platforms offer the potential to significantly increase the efficacy of sorafenib therapy for HCC while reducing systemic exposures via targeted image-guided transcatheter delivery. Quantitative approaches for imaging sorafenib-eluting microsphere delivery may be critical to permit early prediction of response thus prompting adjustments to treatment regimens as needed (additional infusions or adoption of alternative therapies). During this pre-clinical project we seek to develop a powerful new approach for image-guided catheter-directed delivery of sorafenib to liver tumors. We will address the following Specific Aims in a well-established VX-2 rabbit model of liver cancer: Aim 1: Characterize the relationship between poly(D,L-lactide-co-glycolide) (PLG) microsphere fabrication methods, sorafenib and contrast agent loading, size distribution, release kinetics, and MRI properties. Aim 2: Optimize methods for in vivo MRI of SPIO-labeled sorafenib-eluting PLG microspheres and validate that these methods permit accurate quantification of transcatheter delivery to liver tumors. Aim 3: Validate that sorafenib-eluting microspheres inhibit angiogenesis and tumor growth, compare outcomes in liver tumors treated with sorafenib-eluting microspheres, bland embolization, and sorafenib chemo- embolization (drug infusion without microsphere encapsulation), and finally compare MRI measurements of transcatheter microsphere delivery to the elicited therapeutic responses.